INDUCTION OF DELAYED HYPERSENSITIVITY TO SIV

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The development of a safe and effective HIV vaccine is a formidable task. Both antibody and cytotoxic T cell responses to HIV are generated during the infection, but these responses cannot ultimately control the infection or prevent progression to fatal immunodeficiency in the majority of infected individuals. This suggests that there is a reservoir of infected cells that are not recognized or eliminated by these two classical antiviral immune mechanisms. We hypothesize that a novel immune response, one that is not induced during the natural infection, could be effective as a vaccine - induced immune mechanism, giving the vaccinated host an additional antiviral effector mechanism prior to exposure to HIV. This candidate immune response, delayed type hypersensitivity (DTH), is a key controlling immune response in other viral and intracellular bacterial infections, particularly in human infections with tuberculosis and leprosy. Using the SIV/macaque animal model of HIV infection and AIDS, the goal of this small research grant proposal is to induce a DTH response to SIV antigens in rhesus monkeys. SIv antigen-pulsed dendritic cells will be used to direct the effector response toward DTH. An in vitro culture system will be developed to model the DTH response as the control of productive SIV infection in rhesus monocyte/macrophage by autologous, immune T cells. If antigen specific and MHC-restricted responses are detected in immunized animals, they will be challenged by mucosal inoculation of pathogenic SIVmac251. The outcome of challenge will be assessed by quantitative viral load measurements, antiviral immune responses and pathologicchanges in tissues. If antiviral DTH is a protective immune response to SIV, significant reduction in viral load during the acute stage of infection, enhanced DTH and CTL responses and a delayed neutralizing antibody response are expected. In addition, the pathologic changes of disseminated SIV infection in peripheral lymphoid tissues should be significantly reduced. These outcomes would support the concept of antiviral DTH as a protective immune response to target with a novel HIV vaccine.